Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VLA-4 (a4b1), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis.
Thus, compounds which inhibit the interaction between xcex14-containing integrins, such as VLA-4 and VCAM-1, will be useful as therapeutic agents for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), pulmonary inflammation (e.g., asthma), and inflammatory bowel disease (IBD).
It has been discovered that compounds of the formula: 
and the pharmaceutically acceptable salts and esters thereof wherein X, Xxe2x80x2, Z and Y are as defined below, inhibit the binding of VCAM-1 to VLA-4 and so would be useful in treating inflammatory diseases in which such binding acts to bring on the disease.
As used in this specification, the term xe2x80x9clower alkylxe2x80x9d, alone or in combination (for example, as part of xe2x80x9clower alkanoyl,xe2x80x9d below), means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and substituted amino, e.g., lower alkoxycarbonyl amino. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 2-methoxypropyl, 3-oxobutyl, cyanomethyl, trifluoromethyl, 2-nitropropyl, benzyl, including p-chloro-benzyl and p-methoxy-benzyl, and 2-phenyl ethyl.
The term xe2x80x9ccycloalkylxe2x80x9d means an unsubstituted or substituted 3- to 7-membered carbacyclic ring. Substitutents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term xe2x80x9cheterocycloalkylxe2x80x9d means an unsubstituted or substituted 5- to 6-membered carbacyclic ring in which one or two of the carbon atoms has been replaced by heteroatoms independently selected from O, S and N. Preferred heterocycloalkyl groups are pyrrolidinyl and morpholinyl.
The term xe2x80x9clower alkoxyxe2x80x9d means a lower alkyl group (as defined above) bonded through an oxygen atom. Examples of unsubstituted lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term xe2x80x9clower alkylthioxe2x80x9d means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group.
The term xe2x80x9carylxe2x80x9d means a mono- or bicylic aromatic group, such as phenyl or naphthyl which is unsubstituted or substituted by conventional substituent groups. Preferred substitutents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, heteroaryl (especially tetrazolyl), lower alkynyl and lower alkanoylamino. Examples of aryl groups that may be used in accordance with this invention are unsubstituted phenyl, m- or o-nitrophenyl, p-tolyl, m- or p-methoxyphenyl, 3, 4-dimethoxyphenyl, p-chlorophenyl, p-cyanophenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, m-perfluorophenyl, 1-naphthyl, m- or p-2-methyltetraozolyl, and the like.
The term xe2x80x9carylalkylxe2x80x9d means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl or heteroaryl group as herein defined. Any conventional arylalkyl may be used in accordance with this invention, such as benzyl, 2-phenyl ethyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d means an aryl group, as hereinbefore defined which is bonded via an oxygen atom. The preferred aryloxy group is phenoxy.
The term xe2x80x9cheteroarylxe2x80x9d means an unsubstituted or substituted 5- or 6-membered monocyclic hetereoaromatic ring or a 9- or 10-membered bicyclic hetereoaromatic ring containing 1, 2, 3 or 4 hetereoatoms which are independently N, S or O. Examples of hetereoaryl rings are pyridine, benzimidazole, indole, imidazole, thiophene, isoquinoline, quinzoline, tetrazole, and the like. Substitutents as defined above for xe2x80x9carylxe2x80x9d are included in the definition of heteroaryl. The wide variety of heteroaryl groups useful in accordance with the invention is illustrated by Examples 56, 57, 74, 364 and 381-386.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d means a lower alkoxy group bonded via a carbonyl group. Examples of alkoxycarbonyl groups are methoxycarbony, ethoxycarbonyl, t-butoxycarbonyl and the like.
The term xe2x80x9clower alkylcarbonyloxyxe2x80x9d means lower alkylcarbonyl groups bonded via an oxygen atom, for example an acetoxy group.
The term xe2x80x9clower alkanoylxe2x80x9d means lower alkyl groups bonded via a carbonyl group and embraces in the sense of the foregoing, definition groups such as acetyl, propionyl and the like. Where the lower alkyl portion of the lower alkanoyl group is substituted, the preferred substitutents are methoxy, trifluoro, phenyl, cyclopentyl, methoxycarbonyl, amino and t-butoxycarbonylamino.
The term xe2x80x9clower alkylcarbonylaminoxe2x80x9d means lower alkylcarbonyl groups bonded via a nitrogen atom, such as acetylamino.
The term xe2x80x9caroylxe2x80x9d means an mono- or bicyclic aryl or heteroaryl group bonded via a cabonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, m-perfluromethyl-benzoyl, p-methoxy-benzoyl, 2-naphthoyl, groups of the formula: 
and the like.
The present invention comprises a compound of the formula: 
and the pharmaceutically acceptable salts and esters thereof.
In accordance with the invention, Z is hydrogen or lower alkyl (preferably hydrogen), one of X and Xxe2x80x2 is hydrogen, halogen, or lower alkyl (Xxe2x80x2 is preferably hydrogen), and the other (preferably X) is a group X-6, X-7 or X-10 as described below. Y is a group Y-1 or Y-2 as described below.
Y-1 is a group of the formula: 
wherein:
R22 and R23 are independently aryl, heteroaryl or lower alkyl which is unsubstituted or substituted by one or more chloro, bromo, nitro, hydroxy, lower alkoxy, aryl, lower alkanoyl, aroyl or cyano,
R24 is aryl, cyano, alkylsulfonyl or lower alkyl or alkenyl unsubstituted or substituted by an aryl or heteroaryl ring, and when R22 is aryl and R23 is aryl or lower alkyl, hydrogen, and
the total number of carbon atoms in R22, R23 and R24 is from 6 to 14.
In Y-1, R22 and R23 are preferably lower alkyl or phenyl, and R24 is preferably lower alkyl except when R22 is aryl and R23 is aryl or lower alkyl, then R24 is preferably hydrogen.
However, Y is preferably the group Y-2 which is a 3-7 membered ring of the formula: 
wherein:
R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94,
R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio , lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula xe2x80x94NR28R29, wherein:
R28 is hydrogen or lower alkyl,
R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonylaminocarbonyl, lower alkanoyl, aroyl, heteroaroyl, perfluoro lower alkanoyl, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or lower alkyaminothiocarbonyl,
or
R28 and R29 taken together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered saturated heterocyclic ring containing one or two heteroatoms with the second heteroatom being O, S, or Nxe2x80x94R27;
Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fxe2x80x94, or when f=0, a bond, the dotted line is a second bond which is present or absent,
R27 is hydrogen, lower alkyl, aryl, lower alkanoyl, aroyl, or lower alkoxycarbony, the carbon atoms in the ring are unsubstituted or substituted by lower alkyl or halogen,
e is an integer from 0 to 4, and
f is an integer from 0 to 3.
Q is preferably xe2x80x94(CH2)f or, when f=0, a bond. When R25 is a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is preferably aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, nitro, or R26 is a group of formula xe2x80x94NR28R29 wherein R28 is hydrogen or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoyl, lower alkyl sulfonyl, lower alkylaminocarbonyl, heterocycloalkyl carbonyl, arylaminocarbonyl, or R28 and R9 taken together with the nitrogen to which they are attached form a 4, 5 or 6-membered saturated heterocyclic ring which can contain one oxygen atom. When R26 is aryl, it is especially phenyl unsubstituted, mono-substituted by chloro, methoxy, cyano, or tetrazolyl which is unsubstituted or substituted by methyl, or is phenyl di-substituted by methoxy.
The group X-6 is of the formula: 
wherein:
R1 is hydrogen or lower alkyl,
R15 is hydrogen, halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, alkylthio lower alkyl, alkylsulfinyl lower alkyl, alkylsufonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy or a group of the formula R17xe2x80x94Cxe2x89xa1Cxe2x80x94,
R16 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio,
R17 is hydrogen, aryl, heteroaryl, or lower alkyl which is unsubstituted or substituted by OH, aryl, or heteroaryl, and
a is 0 or 1.
The groups R15 and R16 are preferably independently hydrogen, lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, cyano or phenoxy. R1 is preferably hydrogen and a is preferably 0.
X-7 is a group of the formula: 
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S,
or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
a, R1, R15 and R16 are as above, and
R30 is absent or is hydrogen or lower alkyl.
Het is preferably a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. When Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as the heteroatoms. R15 is preferably, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl (especially unsubstituted phenyl); R16 is perferably hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R30, when present, is preferably hydrogen or lower alkyl.
The group X-10 is of the formula: 
wherein:
R18 is hydrogen, substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl. heteroaryl alkyl,
R19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R20 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, carboxyl lower alkanoyl, aroyl, aryloxylower alkanoyl.
R18 is preferably phenyl wherein the phenyl ring is unsubstituted or monosubstituted by lower alkoxy or halogen, or is phenyl lower alkyl. R19 is preferably lower alkyl, which is unsubstituted or substituted by pyridyl or phenyl wherein the phenyl ring is unsubstituted or monosubstituted by lower alkoxy or halogen. R20 is preferably lower alkanoyl.
The compounds of the invention include the pharmaceutically acceptable salts and esters thereof. Certain prefered esters of the invention were discovered which are useful to improve bioavailabilty of compounds of this invention. These preferred esters are of the formula: 
wherein X, Xxe2x80x2, Z and Y are as described above, and R31 is lower alkyl, or R31 is a group of formula P-1: 
wherein:
R32 is hydrogen or lower alkyl,
R33 is hydrogen, lower alkyl, aryl,
R34 is hydrogen or lower alkyl,
h is an integer from 0 to 2,
g is an integer from 0 to 2,
the sum of h and g is 1 to 3; or
R31 is a group of formula P-2: 
xe2x80x83wherein:
R32, g, and h are as previously defined,
T is O, S, xe2x80x94(CH2)jxe2x80x94, a bond (when j=0) or a group of the formula Nxe2x80x94R35,
R35 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, and
j is 0, 1 or 2.
R31 is preferably ethyl or 2-(4-morpholinyl)ethyl.
The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.
The especially preferred groups Y-1 are of the formula: 
The especially preferred groups Y-2 are of the formulas shown in the following table:
The especially preferred groups X-6 are of the formula: 
The especially preferred groups X-7 are of the formula: 
The especially preferred groups X-10 are of the formula: 
The compounds of the invention inhibit the binding of VCAM1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes (xe2x80x9cVLA-4-expressing cellsxe2x80x9d). The binding of VCAM-1 and fibronectin to VLA-4 on such cells is known to be implicated in certain disease states, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and particularly in the binding of eosinophils to pulmonary endothelium which is the cause of the pulmonary inflammation which occurs in asthma. Thus, the compounds of the present invention can be used as medicaments for the treatment of disorders which are knows to be associated with such binding, and especially would be useful for the treatment of asthma.
Furthermore, compounds of the invention also inhibit the binding of VCAM-1 and MadCAM to the cellular receptor alpha4-beta7, also known as LPAM, which is expressed on lymphocytes, eosinophiles and T-cells. While the precise role of alpha4-beta7 interaction with various ligands in inflammatory conditions such as asthma is not completely understood, compounds of the invention which inhibit both alpha4-beta1 and alpha4-beta7 receptor binding are particularly effective in animal models of asthma. Furthermore, work with monoclonal antibodies to alpha4-beta7 indicate that compounds which inhibit alpha4-beta7 binding to MadCAM or VCAM are useful for the treatment of inflammatory bowel disease. They would also be useful in the treatment of other diseases in which such binding is implicated as a cause of disease damage or symptoms.
The compounds of the invention can be administered orally, rectally, or parentally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations, or as an aerosol for the treatment of pulmonary inflammation. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.
Intravenous, intramuscular, oral or inhalation administration is a preferred form of administration. The dosages in which the compounds of the invention are administered in effective amounts depend on the nature of the specific active ingredient, the age and the no requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. Thus, the invention further comprises a method of treating a host suffering from a disease in which VCAM-1 or fibronectin binding to VLA-4-expressing cells is a causative factor in the disease symptoms or damage by administering an amount of a compound of the invention sufficient to inhibit VCAM-1 or fibronectin binding to VLA-4-expressing cells so that said symptoms or said damage is reduced. In general, dosages of about 0.1-100 mg/kg body weight per day are preferred, with dosages of 1-25 mg/kg per day being particularly preferred, and dosages of 1-10 mg/kg body weight per day being especially preferred.
The invention further comprises pharmaceutical compositions which contain a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. Tablets or granulates can contain a series of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavour-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substances, e.g., water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.
Oral unit dosage forms, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of a compound of the invention.
The compounds of the present invention may be prepared by any conventional means. In reaction Scheme 1, a compound of formula 1 in which R1 is hydrogen or lower alkyl, and which is a known compound or can be prepared by standard methodology, is treated with a reducing agent capable of selectively reducing a nitro group in the presence of a benzylic alcohol. This procedure is advantageously carried out in the presence of a derivatizing agent of the formula R2xe2x80x94OCOX wherein X is a leaving group and R2 is tert-alkyl, benzyl or the like so as to form a readily cleavable protecting group, thus leading directly to a compound of formula 2. For example, this procedure can be conveniently carried out by catalytic hydrogenation of 1 over Pd(C) in ethyl acetate in the presence of di-tert-butyl dicarbonate to give a derivative of 2 in which R2 is tert-butyl.
Conversion to an aldehyde of formula 3 can be carried out using an one of a variety of oxidizing agents capable of oxidizing a benzylic alcohol to the corresponding aldehyde, for example activated manganese dioxide in a suitable solvent, for example dichloromethane. Reaction of 3 to give a dehydroamino acid of formula 5 can be effected by treatment with a Wittig reagent of formula 4 in which R3 is lower alkyl and R4 is an alkoxy group, for example benzyloxy- or tert-butoxy- or represents a portion of one of the acyl groups of the compounds of the invention, for example substituted lower alkyl or substituted cycloalkyl. For example treatment of 3 with (xc2x1)-N-(benzyloxycarbonyl)-xcex1-phosphonoglycine trimethyl ester in the presence of a suitable base for example tetramethyl guanidine leads directly to a dehydroamino acid of formula 5, R3=methyl and R4=benzyloxy. Enantioselective reduction of 5 to the L-amino acid 6 can be effected by use of a number of reducing agents suitable for the purpose, for example, the recently described ethyl-DuPHOS rhodium reagent (Burk, M. J., Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125) using essentially the literature procedure. 
One process for the conversion of compounds of structure 6 into compounds of the invention is shown in Reaction Scheme 2. The protecting group incorporating R2 can be removed under conditions dependent on the particular choice of R2 as well as R3 and R4. The choice of these groups will be dependent on the particular target compound. A variety of common protecting groups and their use are described in xe2x80x9cT. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, Wiley Interscience, New York, 1991xe2x80x9d For example when R2 is a tert-butyl group and R3 is lower alkyl and R4 is either a benzyloxy group or represents a portion of one of the acyl groups of the compounds of the invention, for example substituted lower alkyl or substituted cycloalkyl, treatment with trifluoroacetic acid either neat or in dichloromethane solution in the presence of suitable scavengers, for example, triethylsilane or anisol leads to a compound of formula 7. This compound can be coupled with a carboxylic acid of formula 8 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 9. In the carboxylic acid of formula 8, R5 may represent a substituted alkyl group, a substituted aromatic ring, or a substituted heteroaromatic ring. R5 may also incorporate suitably protected reactive functionalities to permit final conversion into compounds of the invention. The choice and use of such groups will be apparent to those skilled in the art. 
Depending on the choice of R4 and whether an ester or acid is the final goal of the synthesis, compound 9 may be a compound of the invention or in the case that R4 is a protecting group, for example, a benzyloxy group, it may be removed under appropriate conditions, for example by catalytic hydrogenation over Pd(C) in a suitable solvent such as a lower alcohol to give a compound of formula 10. This intermediate can be coupled with a carboxylic acid of formula 11 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 12. In the carboxylic acid of formula 11, R6 may represent a portion of a compound of the invention, for example, a substituted alkyl or substituted cycloalkyl. These compounds are known compounds or can be prepared by known methods. R6 may also incorporate suitably protected reactive functionalities to permit final conversion into compounds of the invention. The choice and use of such groups will be apparent to those skilled in the art. General methods for the preparation of such compounds are illustrated in Reaction Scheme 13. If the acid 13 is the target compound, conversion of a compound of formula 12 can be effected using standard hydrolysis conditions appropriate for the particular choice of R3 and any functional groups present as part of R5 and R6. In the case where R3 is lower alkyl, treatment with an alkali metal hydroxide, for example lithium hydroxide in aqueous THF is generally effective.
In reaction Scheme 3, a compound of formula 14 in which R7 is a lower alkyl group which may serve as a protecting group or a group suitable for use in a prodrug for example methyl, ethyl, tert-butyl or the like or represents a connection to a solid phase resin, for example a Wang resin, is coupled with a carboxylic acid of formula 11 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 15. Reduction of the nitro group of 15 can be effected by catalytic hydrogenation for example using Pd(C) as a catalyst or by treatment with a standard reducing agent, for example SnCl2. The resulting compound of structure 16 is useful as a key intermediate for several series of compounds. In the instance highlighted in Scheme 3, it can be coupled with an acid of formula 8 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 17. Compound 17 may be a compound of the invention depending on the nature of R7 or may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example in the case where R7 is lower alkyl, by hydrolysis by treatment with excess alkali metal hydroxide, such as lithium hydroxide in aqueous alcohol. When R7 represents a resin suitable for solid phase synthesis, appropriate hydrolysis conditions will depend on the choice of resin. In the case of Wang resin, treatment with trifluoroacetic acid in the presence of appropriate scavengers will lead to an acid of formula 18. 
In a method particularly well suited for solid phase synthesis, an Nxe2x80x2-Alloc-amino-Nxcex1-Fmoc protected phenylalanine derivative of formula 19 can be coupled to a resin suitable for solid phase synthesis, for example, a Wang resin using standard coupling procedures, for example, by forming a mixed anhydride with 2,6-dichlorobenzoyl chloride and carrying out the coupling reaction in a polar, aprotic solvent such as N-methyl pyrrolidinone to give a compound of structure 20 in which R7xe2x80x2 represents the resin. The Alloc group may be removed by standard methods, for example by treatment with a reducing agent such as nBu3SnH in the presence of a catalyst which is a source of Pdo, for instance, Pd(Ph3P)2Cl2 to give an amine derivative of structure 21. This compound can be coupled with a carboxylic acid of formula 8 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 22. The Fmoc protecting group may be removed from 22 using standard base treatment well known to those practicing peptide chemistry, for example with piperidine in DMF, to afford an amine of formula 23. The resulting compound 23 can be coupled with a carboxylic acid of formula 11 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 24. Finally the compound of structure 24 can be cleaved from the resin under conditions dependent on the particular choice of resin. For example, in the case of a Wang resin, acid treatment with trifluoroacetic acid in dichloromethane in the presence of scavengers as necessary will afford a compound of formula 18.
Depending on the particular synthetic target, the order of removal of the protecting groups from 19 may be altered so that the Fmoc group is first removed, coupling of the resulting amine with an acid of formula 11 is carried out followed by removal of the Alloc group and coupling of the product with an acid of formula 8 and cleavage from the resin. Also the choice of protecting groups can be modified to reflect the reactivities of the resin and the nature of any functional groups incorporated into R5 and R6. 
Compounds derived from 3- or 4-(alkylamino)phenylalanine derivatives can be prepared as outlined in Reaction Scheme 5. A compound of formula 16 or 7 may be treated with diazomethane in a suitable solvent, for example, ethyl ether to give products of formulas 25 and 26 respectively in which R8 is methyl. Alternatively, the compound of structure 16 or 7 may be treated with an lower alkyl aldehyde or ketone, for example acetone, to give an intermediate Schiffs base which is in turn subjected to catalytic hydrogenation or reduction with sodium cyanoborohydride in the presence of an organic acid, for example acetic acid to give a compound of formula 25 or 26 in which R8 is lower alkyl other than methyl. Conversion of compounds 25 or 26 to prodrug esters 27 or 28 or to the corresponding acids 29 or 30 respectively can be carried out as described above in Reaction Schemes 2 and 3. 
For the preparation of 3- or 4-sulfonylamino phenylalanine derivatives, compounds of formula 7, 16, 25 or 26 may be reacted with a sulfonyl chloride of formula 31, in which R9 is a substituted aryl or heteroaryl moiety, in an inert solvent, for example dichloromethane in the presence of a non-nucleophilic base, for example triethylamine or pyridine at about 0xc2x0 C. to room temperature to give compounds of structure 32 or 33 respectively as illustrated in Reaction Scheme 6 for compounds 7 and 26. These can be further converted to compounds of formulas 34 and 35 if desired using the general methods described above in Reaction Schemes 2 and 3. Furthermore, the group R4COxe2x80x94 may replaced by a group R6COxe2x80x94 using the general chemistry described in scheme 2.
For the preparation of compounds derived from 3- or 4-aminomethylphenylalanine, the procedure shown in Reaction Scheme 7 may be employed. A 3- or 4-hydroxymethyl benzoate of formula 36 in which R10 is lower alkyl, which are known compounds, or can be prepared by known methods, is treated with a silylating agent in which R11-R13 are lower alkyl or phenyl, for example tert-butyldimethylsilyl chloride in an inert solvent, for example dimethylformamide in the presence of imidazole at about 0xc2x0 C. to give a silyl protected compound of formula 37. Reduction of 37 may be carried out using a variety of suitable reducing agents, for example, lithium aluminum hydride in an inert solvent such as ether or tetrahydrofuran at a temperature of about 0xc2x0 C. followed by an aqueous workup to give an intermediate alcohol which can be oxidized by any of several oxidizing agents suitable for oxidizing benzyl alcohols to the corresponding aldehydes, for example activated manganese dioxide, to give an aldehyde of formula 38. Monosilyl protected diols are alternatively available from 3- or 4-hydroxymethylbenzylalcohols by monosilylation and separation of the side products. Alternatively, an ester of formula 37 may be reduced directly to an aldehyde of formula 38 using diisobutylaluminum hydride at low temperature, for example at xe2x88x9278xc2x0 C.
Reaction of 38 to give a dehydroamino acid of formula 39 can be effected by treatment with a Wittig reagent of formula 4 in which R3 is lower alkyl and R4 is an alkoxy group, for example benzyloxy- or tert-butoxy- or represents a portion of one of the acyl groups of the compounds of the invention, for example substituted lower alkyl or substituted cycloalkyl. For example treatment of 38 with (xc2x1)-N-(benzyloxycarbonyl)-xcex1-phosphonoglycine trimethyl ester in the presence of a suitable base for example tetramethyl guanidine leads directly to a dehydroamino acid of formula 39, R3=methyl and R4=benzyloxy. Enantioselective reduction of 39 to the L-amino acid 40 can be effected by use of one of a number of reducing agents suitable for the purpose, for example, the recently described ethyl-DuPHOS rhodium reagent. It will be readily apparent to those skilled in the art that the optimal procedure for the further conversion of 40 into compounds of the invention will depend on the choices of R4 and R3. For the case wherein R3 is lower alkyl and R4 is benzyloxy, conversion to an amine of formula 41 can be conveniently effected by catalytic transfer hydrogenation of 40 over Pd(C) in a suitable solvent, for example, methanol in the presence of ammonium formate as the reducing agent. Acylation of 41 with a carboxylic acid of formula 11 can be carried as described above in Reaction Scheme 2 to give a compound of formula 42. Conditions for removal of the silyl protecting group will depend on the particular choice of R11-R13. In the case of R11, R12=methyl and R13=tert-butyl, this group is readily removed by treatment with a strong acid, for example hydrochloric acid in an appropriate solvent for the choice of R3, for example where R3 is methyl, methanol.
The resulting benzylic alcohol of formula 43 can be converted to an amine of formula 45 using procedures well established for similar transformations. For example, the alcohol of formula 43 can be converted to a leaving group, for example a mesylate by treatment with methane sulfonyl chloride in the presence of a proton acceptor, for example pyridine, followed by displacement with an alkali metal azide, for example sodium azide in a polar aprotic solvent such as dimethylformamide. Alternatively, the transformation from 43 to an azide of formula 44 can be carried out directly by treatment with diphenyl phosphorazidate as described in: Thompson, A. S.; Humphrey, G R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886-5888. Reduction of the azide 44 to an amine of formula 45 can be carried out by a number of means suitable for the conversion of azides to amines, for example by treatment with a phosphine, for example triphenyl phosphine in an inert solvent such as dichloromethane or THF followed by an aqueous workup or by catalytic hydrogenation over an appropriate catalyst, for example Pd(C) in a solvent suitable for catalytic hydrogenations such as a lower alkanol or tetrahydrofuran. The resulting amine of formula 45 can be converted into the corresponding compounds of the invention using the procedures applicable to free amines described in the other reaction schemes. For example, coupling of 45 with a carboxylic acid of formula 8 under the conditions described in Reaction Scheme 2 leads to an amide of formula 46 which may be further converted to an acid of formula 47 if desired by base catalyzed hydrolysis as described in Reaction Scheme 2. 
For the synthesis of urea derivatives, a compound of formula 26 can be treated with an isocyanate of formula 49, wherein R14 is substituted aryl, substituted heteroaryl or substituted lower alkyl with potentially reactive substituents protected as appropriate using conventional protecting group strategies, in a suitable inert solvent, for example dichloromethane, to give a urea of formula 50. More generally, a compound of formula 26 can be treated with a phosgene equivalent, for example, triphosgene in an inert solvent such as dichloromethane in the presence of a non-nucleophilic proton acceptor, for example diisopropylethylamine, to give an intermediate of formula 48. Subsequent treatment of a compound of formula 48 with an amine of formula 51 in which R15 and R16 are independently hydrogen, substituted lower alkyl substituted aryl, substituted heteroaryl or taken together form a substituted 5, 6 or 7 membered ring leads to a compound of formula 52. Further conversion, if necessary, of 50 or 52 to compounds of the invention can be carried out as described in Reaction Scheme 5. 
For the synthesis of imides, an aminophenylalanine derivative of structure 53 in which R1 is hydrogen or lower alkyl, R6 is as previously defined and R7xe2x80x3 is hydrogen or a readily cleavable group such as substituted benzyl, tert-butyl, allyl, or the like, or in the event that a prodrug ester is desired as the final product, is that ester group, for example ethyl, is employed. Compounds of formula 53 can be readily obtained from intermediates described above in Reaction Scheme 2. Reaction of a compound of formula 53 with a cyclic anhydride of formula 54 in an inert solvent, for example dichloromethane leads to a ring opened intermediate of formula 55. The structure implied by 54 includes bicyclic molecules which may incorporate fused aromatic or heteroaromatic rings. In place of 54, it is also possible to use dicarboxylic acids which are capable of forming cyclic imides. In the latter case, a condensing agent must be employed in the first step, for example carbonyl diimidazole. Treatment of the compound of formula 55 with a reagent such as carbonyl diimidazole capable of effecting cyclodehydration leads to an imide of formula 56. Further manipulation of functional groups which were present on the anhydride of formula 54 and modification of R7xe2x80x3 may be carried out on compound 56 as desired to obtain further analogs using standard chemistry which is compatible with the presence of the imide functionality.
For the synthesis of compounds of the invention in which R1 is halogen, preferably chloro, the appropriate halogen atom can be incorpoarted into the starting material or inserted at various points during the course of the synthesis depending on the nature of the additional functionality in the molecule. A chlorine atom can be incorporated into the compound of structure 1, shown in scheme 1 and carried through to the compounds of the invention by avoiding reagents which would be expected to react with a halogen atom For example a compound of formula 6 in which R1 is hydrogen can be treated with a mild chlorinating agent, for example, N-chlorosuccinimide in the presence of a proton acceptor, for example, sodium acetate to give the corresponding compound of formula 6 in which R1 is chloro. In the case where 6 is derived from 3-amino-L-phenylalanine, a mixture of regioisomers may ensue which may be separated at a convenient point in the overall synthesis. Other intermediates described in the above schemes may be more suitable starting materials for halogenation for a particular target molecule. The particular merits of individual candidate starting materials will be apparent to those skilled in the art. 
For the synthesis of the thiazolidinones of formula 62 described in reaction scheme 10, an aminophenylalanine derivative of structure 16, in which R6 and R7 are as previously defined may be employed. Reaction of 16 with an xcex1-mercapto carboxylic acid of formula 59 in which R20 can be hydrogen, lower alkyl or aryl, for example xcex1-mertcapto acetic acid, and an aldehyde of formula 60 in which R21 can be lower alkyl, arylalkyl or a substituted aryl group, for example benzaldehyde, in an appropriate solvent such as benzene, THF or a lower alcohol, for example methanol, in the presence of a water scavenger such as 4 xc3x85 molecular sieves at 60 to 80xc2x0 C. provides compound of formula 61. Compound 61 may be a compound of the invention depending on the nature of R7 or may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example in the case where R7 is lower alkyl, by treatment with excess alkali metal hydroxide, such as sodium hydroxide in aqueous alcohol. When R7 represents a resin suitable for solid phase synthesis, the appropriate hydrolysis conditions will depend on the choice of resin. In the case of Wang resin, treatment with trifluoroacetic acid in the presence of appropriate scavengers will lead to an acid of formula 62. The sequence may be initiated with related anilines, for example a compound of formula 7 in which R1 is lower alkyl or halogen to give the corresponding thiazolidinones. 
For the synthesis of imidazolidinones of formula 67 shown in reaction scheme 11, an aminophenylalanine derivative of structure 16 in which R6 and R7 are as previously defined may be employed. Compound 16 can be readily obtained through the synthesis described in reaction scheme 3. This compound can be coupled with a N-protected xcex1-amino acid of formula 63, in which R22 can be a lower alkyl or an aryl group, R23 can be a natural or unnatural D- or L-xcex1-amino acid side chain or R22 and R23 together can form a ring, for example a proline or pipicolinic acid ring and R24 may be a standard amine protecting group suitable for the particular selection of R6, R7, R22, and R23 for example tert-butoxycarbonyl. The coupling reaction can be effected using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 64. Depending on the nature of protecting group R24, an appropriate deprotection method is employed to give a compound of formula 65. In the event that the protecting group R24 is a Boc group, the deprotection can be carried out by the reaction of 64 with HCl in dioxane at room temperature. Reaction of compound 65 with an aldehyde of formula 60, in which the R21 is as defined above, in the presence of a water scavenger such as 4 xc3x85 molecular sieves at 60 to 80xc2x0 C. in an appropriate solvent, for example THF, provides a compound of formula 66. Compound 66 may be a compound of the invention depending on the nature of R7 or may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example in the case where R7 is lower alkyl, by hydrolysis by treatment with an alkali metal hydroxide, such as sodium hydroxide in aqueous alcohol to give a carboxylic acid of formula 67. 
For the synthesis of imidazolidinones of formula 68 described in reaction scheme 12, an aminophenylalanine derivative of structure 16 in which R6 and R7 are as previously defined is employed. Compound 16 can be readily obtained through the synthesis described in reaction scheme 3 in the case of R7 is lower alkyl. This compound can be coupled with a N-protected xcex1-amino acid of formula 69, in which R25 can be a natural or unnatural, D- or L-xcex1-amino acid side chain and R26 is a nitrogen protecting group of the type conventionally used in peptide chemistry, for example, a Fmoc group, using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0xc2x0 C. and room temperature to give a compound of formula 70. Depending on the nature of protecting group R26, an appropriate deprotection method is employed to give compound of formula 71. In the case of the protecting group R26 is Fmoc group, it may be removed from 70 using standard base treatment well known to those practicing peptide chemistry, for example with piperidine in DMF, to afford an amine of formula 71. The compound 71 can then react with an aldehyde 60, in which R21 is as previously defined, in the presence of a water scavenger such as 4 xc3x85 molecular sieves in an appropriate solvent such as dichloromethane or THF at 25-80 xc2x0 C. (bath termperature) to give an imine of formula 72. The imine 72 may then be treated with an acylating agent such as the acyl chloride of formula 74 in which R27 can be an alkyl or aryl group in the presence of a base such DIPEA or DBU in an appropriate solvent such as dichloromethane or THF at 25-80xc2x0 C. (bath temperature) to give an acyl imidazolidinone of formula 73. Other acylating groups may be employed for example, acid anhydrides, and where appropriate, 74 may bear protected substituents which can later be removed at the necessary point in the synthesis. Compound 73 may be a compound of the invention, or depending on the nature of R7 may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example in the case where R7 is lower alkyl, by hydrolysis by treatment with an alkali metal hydroxide, for example sodium hydroxide in aqueous alcohol to give, after acidification, a carboxylic acid of formula 68. The sequence may be initiated with related anilines, for example a compound of formula 7 in which R1 is lower alkyl or halogen to give the corresponding 3-acyl imidazolidinones. 
The acids of formula 11 are known compounds or can be prepared using standard methodologies. For the preparation of substituted alkyl- or cycloalkylcarboxylic acids, alkylation reactions can be employed using an alkali metal dianion of the acid or monoanion of the corresponding ester. For example, a cycloalkyl carboxylic acid ester of formula 75 can be treated with a strong base, for example, lithium diisopropylamide in an inert solvent, for example THF followed by addition of group R28-Lv wherein R28 represents a desired side chain, such as a substituted benzyl, lower alkyl, lower alkoxy alkyl, azidolower alkyl and the like and Lv represents a leaving group such as a bromide, iodide, mesylate or similar group known to participate in ester enolate alkylation reactions. The product ester 76 may be hydrolyzed to the acid 77 using alkali metal hydroxide in a suitable solvent, for example aqueous alcohol. Depending on the nature of R28 and the eventual target, the compound 77 may be a coupled to an amine such as compound 23 and converted to the target directly or R28 may be subject to further manipulation at a suitable point in the synthesis. For example, if R28 is an azido lower alkyl moiety, the azide may be reduced using for example a trialkyl phosphine reagent followed by functionalization of the product amine by alkylation, acylation, sulfonylation and related procedures well known to those skilled in the art. If R29 incorparates a leaving group, for example, a terminal bromine atom, this group may be displaced by an appropriate nucleophile, for example, sodium methyl mercaptide to give in this case, a thioether which may be the desired product or can be itself further manipulated, for example by oxidation to a sulfoxide or sulfone using standard reaction conditions. Other nucleophiles which may be employed to produce intermediates leading to compounds of this invention include: sodium cyanide, sodium methoxide, sodium azide, morpholine and others. When R28 incorporates a ketal group, this group may be hydrolyzed at a convenient point in the synthesis to provide a keto group. This group in turn may be further manipulated, for example by reduction to an alcohol or conversion to derivative such as an oxime. 
General Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. Optical rotations were determined with a Perkin-Elmer model 241 polarimeter. 1H-NMR spectra were recorded with Varian XL-200 and Unityplus 400 MHz spectrometers, using tetramethylsilane (TMS) as internal standard. Electron impact (EI, 70 ev) and fast atom bombardment (FAB) mass spectra were taken on VG Autospec or VG 70E-HF mass spectrometers. Silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh silica gel for flash chromatography; columns were run under a 0-5 psi head of nitrogen to assist flow. Thin layer chromatograms were run on glass thin layer plates coated with silica gel as supplied by E. Merck (E. Merck #1.05719) and were visualized by viewing under 254 nm UV light in a view box, by exposure to I2 vapor, or by spaying with either phosphomolybdic acid (PMA) in aqueous ethanol, or after exposure to Cl2, with a 4,4xe2x80x2-tetramethyldiaminodiphenylmethane reagent prepared according to E. Von Arx, M. Faupel and M Brugger, J. Chromatography, 1976, 120, 224-228.
Reversed phase high pressure liquid chromatography (RP-HPLC)was carried out using either a Waters Delta Prep 4000 employing a 3xc3x9730 cm, Waters Delta Pak 15 xcexcM C-18 column at a flow of 40 mL/min employing a gradient of acetonitrile:water (each containing 0.75% TFA) typically from 5 tp 95% acetonitrile over 35-40 min or a Rainin HPLC employing a 41.4 mmxc3x9730 cm. 8 xcexcM, Dynamax(trademark) C-18 column at a flow of 49 mL/min and a similar gradient of acetonitrile:water as noted above.
Dichloromethane (CH2Cl2), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fisher reagent grade and were used without additional purification except as noted, acetonitrile was Fisher hplc grade and was used as is.
THF is tetrahydrofaran,
DMF is N,N-dimethylformamide,
HOBT is 1-hydroxybenzotriazole,
BOP is [(benzotriazole-1-yl)oxy]tris-(dimethylamino)phosphonium hexafluorophosphate,
HATU is O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU is O-benzotriazole-N,N,Nxe2x80x2,Nxe2x80x2,-tetramethyluronium hexafluorophosphate,
DIPEA is diisopropylethylamine,
DMAP is 4-(N,N-dimethylamino)pyridine
DPPA is diphenylphosphoryl azide
DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene
NaH is sodium hydride
brine is saturated aqueous sodium chloride solution
TLC is thin layer chromatography
LDA is lithium diisopropylamide
BOP-Cl is bis(2-oxo-3-oxazolidinyl)phosphinic chloride
NMP is N-methyl pyrrolidinone